Clean Synthetic Strategies to Biologically Active Molecules from Lignin: A Green Path to Drug Discovery**

Abstract

Deriving active pharmaceutical agents from renewable resources is crucial to increase the economic feasibility of modern biorefineries and promises to alleviate critical supply‐chain dependencies in pharma manufacturing. At the fundamental level, embracing the structural complexity of renewable resources offers hitherto unexploited opportunities for the green synthesis of essential pharmaceuticals, and opens new avenues in drug discovery. In this vein, our multidisciplinary approach combines research in lignin‐first biorefining, sustainable catalysis, and alternative solvents with bioactivity screening, an in vivo efficacy study, and a structural similarity search. The resulting sustainable path to novel anti‐infective, anti‐inflammatory, and anti‐cancer molecules enabled the rapid identification of frontrunners for key therapeutic indications. Most significantly, we discovered an anti‐infective against the priority pathogen Streptococcus pneumoniae, showing efficacy in vivo and promising plasma‐ and metabolic stability. Our established chemocatalytic methods, inspired by the innate structural features of lignin, provide straightforward access to synthetically challenging biologically active molecules of the core dopamine structure, namely tetrahydroisoquinolines, quinazolinones, 3‐arylindoles and the natural product tetrahydropapaveroline. Our diverse array of atom‐economic transformations produce only harmless side‐products and use benign reaction media, such as tunable deep eutectic solvents for modulating reactivity in challenging cyclization steps.

Solvent-triggered directional lignin valorization towards monomeric acetals or lignin polyols

“…The monomeric acetal products produced in this work, which are mainly acetals, have potential applications as precursors for the synthesis of dopamine or pharmaceutical intermediates, as demonstrated in recent publications. 16,40 Additionally, the biphasic system may provide insights for developing specific reactions in organic synthesis. Furthermore, the stabilization of lignin in the biphasic DES reaction led to the formation of functionalized lignin with a significantly higher yield.…”

“…The stabilized active aldehydes formed high yields of cycloacetals, which are a promising stream for pharmaceutical synthesis. [16][17][18] The physical stabilization strategy, which involves the prompt separation of active reaction products, has shown great potential in controllable biorefinery. [19][20][21] The development of biphasic solvent systems plays a crucial role in enabling tailored lignocellulose fractionation, lignin extraction, and carbohydrate transformation processes.…”

“…The stabilized active aldehydes formed high yields of cycloacetals, which are a promising stream for pharmaceutical synthesis. 16–18…”